SMC1A
protein-codingstructural maintenance of chromosomes 1A, the group of MicroRNA protein coding host genes|Cohesin complex|Structural maintenance of chromosomes proteins
Gene summary
Proper cohesion of sister chromatids is a prerequisite for the correct segregation of chromosomes during cell division. The cohesin multiprotein complex is required for sister chromatid cohesion. This complex is composed partly of two structural maintenance of chromosomes (SMC) proteins, SMC3 and either SMC1B or the protein encoded by this gene. Most of the cohesin complexes dissociate from the chromosomes before mitosis, although those complexes at the kinetochore remain. Therefore, the encoded protein is thought to be an important part of functional kinetochores. In addition, this protein interacts with BRCA1 and is phosphorylated by ATM, indicating a potential role for this protein in DNA repair. This gene, which belongs to the SMC gene family, is located in an area of the X-chromosome that escapes X inactivation. Mutations in this gene result in Cornelia de Lange syndrome. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2013]
- SMC1L1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~48.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: XL
Disease ID:MONDO:0010370
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0010370
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0016033
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0026771
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: XL
Disease ID:MONDO:0026771
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0017746
Submitter: Orphanet
Inheritance Pattern: XL
Disease ID:MONDO:0010370
Submitter: PanelApp Australia
Inheritance Pattern: XL
Disease ID:MONDO:0100148
Submitter: ClinGen
*SMC1A* was first reported in relation to X-linked Cornelia de Lange syndrome in 2006 (Musio et al., PMD: 16604071). Variants in *SMC1A* have been reported in individuals with the following disease entities: Cornelia de Lange syndrome 2 (OMIM: 300590) and Developmental and epileptic encephalopathy 85, with or without midline brain defects (OMIM: 301044); both are associated with X-linked dominant inheritance. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found no difference in inheritance pattern and overlapping phenotypes. Therefore, these two disease entities have been lumped into one disease entity, X-linked complex neurodevelopmental disorder. At least 20 missense variants, 1 splicing, and 5 small deletions have been reported in humans. Variants have been found in at least 28 probands in 5 publications (PMIDs: 28166369, 26752331, 24124034, 1660407, 19701948). More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease relationship is also supported by functional alteration in patient cells and protein interactions. In summary, there is definitive evidence supporting the relationship between *SMC1A* and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on June 19, 2019 (SOP Version 6).
Inheritance Pattern: XL
Disease ID:MONDO:0026771
Submitter: G2P
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular; Craniofacial; Musculoskeletal; Neurologic
Intervention: Cardiovascular
Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to SMC1A variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006306.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 2 | 25 | 243 | 6 | 276 | |
| missense | 25 | 72 | 339 | 25 | 5 | 466 |
| nonsense | 30 | 12 | 16 | 58 | ||
| start loss | 0 | |||||
| frameshift | 52 | 20 | 72 | |||
| splice donor/acceptor (+/-2bp) | 11 | 9 | 27 | 47 | ||
| Total | 118 | 115 | 407 | 268 | 11 | 919 |
Highest pathogenic variant AF is 0.00004747844
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006297.2 | 25 | MANE Select | |
| Ensembl | ENSP00000323421.3 | 25 | MANE Select | |
| RefSeq | NP_001268392.1 | 25 | Standard | |
| Ensembl | ENSP00000364489.7 | 25 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| smc1a | Danio rerio | Structure: neural tube Quality: increased occurrence abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Cell cycle - Homo sapiens (human)
- Oocyte meiosis - Homo sapiens (human)
- Cell Cycle
- miRNA Regulation of DNA Damage Response
- miR-targeted genes in epithelium - TarBase
Biological Process
- mitotic sister chromatid segregation
- DNA repair
- sister chromatid cohesion
- mitotic sister chromatid cohesion
- response to radiation
Molecular Function
- chromatin binding
- RNA binding
- protein binding
- ATP binding
- mediator complex binding
Cellular Component
- chromosome, centromeric region
- kinetochore
- condensed chromosome kinetochore
- condensed nuclear chromosome
- nucleus
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000322213
- Coding exons
- 25
- Length
- 48608
- Individuals with no LoFs
- 0
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 0
- Defined
- 0
- p
- 0.00
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 6.45 | 100 | 510 | 0.196 | 0.0000431 | 8229 |
| Missense (PolyPhen) | 14 | 210.32 | 0.066566 | 3237 | ||
| Synonymous | 0.190 | 171 | 174 | 0.982 | 0.0000127 | 2196 |
| Loss of Function | 6.43 | 0 | 48.1 | 0.00 | 0.00000372 | 831 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0 | 0.0 | absent |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0 | 0.0 | absent |
| South Asian | 0 | 0.0 | absent |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in chromosome cohesion during cell cycle and in DNA repair. Central component of cohesin complex. The cohesin complex is required for the cohesion of sister chromatids after DNA replication. The cohesin complex apparently forms a large proteinaceous ring within which sister chromatids can be trapped. At anaphase, the complex is cleaved and dissociates from chromatin, allowing sister chromatids to segregate. The cohesin complex may also play a role in spindle pole assembly during mitosis. Involved in DNA repair via its interaction with BRCA1 and its related phosphorylation by ATM, or via its phosphorylation by ATR. Works as a downstream effector both in the ATM/NBS1 branch and in the ATR/MSH2 branch of S-phase checkpoint. {ECO:0000269|PubMed:11877377}.;
- Disease
- DISEASE: Cornelia de Lange syndrome 2 (CDLS2) [MIM:300590]: A form of Cornelia de Lange syndrome, a clinically heterogeneous developmental disorder associated with malformations affecting multiple systems. Characterized by facial dysmorphisms, abnormal hands and feet, growth delay, cognitive retardation, hirsutism, gastroesophageal dysfunction and cardiac, ophthalmologic and genitourinary anomalies. {ECO:0000269|PubMed:16604071, ECO:0000269|PubMed:17221863, ECO:0000269|PubMed:17273969, ECO:0000269|PubMed:18996922, ECO:0000269|PubMed:19701948, ECO:0000269|PubMed:20358602, ECO:0000269|PubMed:20635401, ECO:0000269|PubMed:24124034}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.251
Intolerance Scores
- LoFtool
- 0.0219
- RVIS EVS
- -0.49
- RVIS percentile EVS
- 22.09
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.988
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Low | Low |
| Primary Immunodeficiency | Medium | Low | Medium |
| Cancer | Medium | Medium | Medium |